Discovering a Combination Therapeutic Approach to Use in the Treatment of Cryptoc

发现治疗隐毛虫病的联合治疗方法

• 批准号: 8542151
• 负责人: MITCHELL W MUTZ
• 金额: $ 34.95万
• 依托单位: AMPLYX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542151
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adverse effects; Africa South of the Sahara; AmBisome; Amphotericin B; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Arrhythmia; Binding Sites; Brain; Cell Wall; Cells; Cessation of life; Cryptococcal Meningitis; Cryptococcus neoformans; Cryptococcus neoformans infection; Cytochrome P450; Cytolysis; Data; Development; Disease; Drug Formulations; Drug Targeting; Eukaryota; Fever; Fluconazole; Flucytosine; Generic Drugs; Genetic; Goals; Growth; HIV; HIV Seropositivity; Headache; Hospitals; Human; Individual; Industrial fungicide; Infection; Inflammation; Injection of therapeutic agent; Left; Leukopenia; Libraries; Lipids; Liposomes; Mammals; Meninges; Nausea; Neoadjuvant Therapy; Neuraxis; North America; Opportunistic Infections; Oral; Orthologous Gene; Outcome; P-Glycoprotein; PDPK1 gene; Patients; Pharmaceutical Preparations; Phosphotransferases; Population; Property; Protein Kinase Inhibitors; Protons; Relative (related person); Sales; Screening Result; Staging; Symptoms; Testing; Therapeutic; Toxic effect; Treatment outcome; Triazoles; Tuberculosis; Yeasts; base; cytotoxicity; design; drug candidate; fungus; improved; in utero; inhibitor/antagonist; kinase inhibitor; mental state; mortality; nephrotoxicity; novel; posaconazole; protein kinase inhibitor; public health relevance; screening; small molecule; theories

DESCRIPTION (provided by applicant): Cryptococcosis is a devastating opportunistic infection caused primarily by Cryptococcus neoformans. Cryptococcosis most often spreads to the brain, causing cryptococcal meningitis (CM), and is fatal if left untreated. CM is the AIDS-defining central nervous system (CNS) illness and occurs in 60-70% of HIV positive individuals worldwide. In sub-Saharan Africa, CM causes more than 500,000 annual deaths among HIV positive patients compared with 350,000 annual fatalities for tuberculosis in the overall population. CM presents with symptoms including severe nausea, headache due to inflammation of the meninges, altered mental status, and fever. Lack of access to the recommended first-line therapeutic combination of amphotericin B/flucytosine (AmB/flucytosine) is a key component of the high mortality rate in the developing world. Access in this setting is hindered by the need for hospital-based i.v. administration of these drugs which lack an oral formulation. Moreover, the mortality rate for HIV-infected acute CM patients is over 20% within 3 months after infection in North America, despite patient access to AmB/flucytosine. Fluconazole, an oral, fungistatic drug, is used after the initial treatment with AmB/flucytosine, and is often used for months after induction therapy. Sales of Gilead's liposomal Ambisome B alone (not counting generic AmB) were $330 million in 2011 while sales of fluconazole exceeded $1 billion annually, prior to 2003. By employing a novel screen for fungicidal compounds, we identified several molecules that target C. neoformans Pkh2-02 kinase. Encouraged by preliminary data demonstrating that orally available Pkh2-02 kinase inhibitors combined with fluconazole have fungicidal activity, we plan to create a novel and efficacious treatment for CM. Aim 1. Employ initial library screening results and SAR to design a small library of Pkh2-02 inhibitors Aim 2. Screen and select compounds for antifungal activity against strains of C. neoformans as monotherapy and combined with fluconazole (FL) or posaconazole (POS), evaluate initial pk properties and cytotoxicity, and iterate library based on observed SAR. Aim 3. Iterate library as needed to generate an additional 40 compounds based on the Aim 2 results to refocus library and perform more detailed pk and pd screens.

描述（由申请人提供）：隐球菌病是一种毁灭性的机会性感染，主要由加密型新形象棒引起。隐球菌病通常会传播到大脑，导致隐球菌脑膜炎（CM），如果未治疗，则致命。 CM是定义中枢神经系统（CNS）疾病的艾滋病，发生在全球60-70％的艾滋病毒阳性个体中。在撒哈拉以南非洲，CM在艾滋病毒阳性患者中造成500,000多人死亡，而每年350,000例死亡人数死亡。 CM表现出症状，包括严重的恶心，由于脑膜炎症引起的头痛，精神状态改变和发烧。缺乏进入推荐的一线治疗组合，两性霉素B/氟替辛（AMB/氟甲胺）是发展中国家高死亡率的关键组成部分。在这种情况下的访问受到基于医院的静脉注射的需求所阻碍。这些药物缺乏口服配方的药物。此外，尽管患者使用AMB/氟胞嘧啶，但感染HIV感染的急性CM患者的死亡率在感染后3个月内的死亡率超过20％。氟康唑是一种口服，fungistatic的药物，在用AMB/氟甲霉素进行初始治疗后，通常在诱导治疗后几个月使用。吉利德（Gilead）的脂质体Ambisome B的销售额（不计算通用AMB）在2011年为3.3亿美元，而氟康唑的销量每年超过2003年之前的销售额超过10亿美元。通过采用新颖的真质化合物屏幕，我们确定了几个靶向Neooformans PKH2-02-02-02-02-02-02-02 Kinase的分子。在初步数据的鼓励下，表明口服可用的PKH2-02激酶抑制剂与氟康唑相结合具有杀真菌活性，我们计划为CM创建一种新颖有效的治疗方法。 AIM 1。采用初始图书馆筛选结果和SAR设计PKH2-02抑制剂的小库Aim 2。筛查和选择用于针对Neoformans菌株的抗真菌活性的化合物作为单一疗法，并与氟康唑（FL）或氟康唑（POS）（POS）结合，评估初始PK属性和细胞毒性基于pk properties and ytotoxicities and tytotoxicity and Itcors comports sarsepersement sarsepersearsementer和Itereserate sarseasere sarsepersementersementersepers。 AIM 3。根据需要迭代库，以基于AIM 2的结果生成40种化合物，以重新集中库并执行更详细的PK和PD屏幕。